The basis for ethanol-related alterations in the organism is intimately linked to the metabolism of ethanol and the changes ethanol elicits in normal metabolic pathways. While this principle is applicable in all organs affected by ethanol, the response in different tissues can vary widely. Thus, a study of the metabolism associated with ethanol can be focused on different responses in different organs. The studies encompassed in this application for a Senior Scientist award are directed toward the effects of ethanol on metabolic systems in liver and brain. With regard to the liver studies, the major goal is to relate alterations in metabolism to development of alcoholic liver disease. Included are studies of the effects of ethanol on 1) the integrity of the mitochondrial oxidative phosphorylation system and 2) the synthesis of ATP via the glycolytic pathway. Experiments are included to examine how ethanol-elicited alterations in the above mechanisms affect the structural and functional integrity of the hepatocyte. The interplay between oxidative stress and cellular energy state in the ethanol- related loss of hepatocyte viability will also be evaluated. The metabolic studies in the brain, which are a new area for me, are focused on establishing alterations in glucose and neurotransmitter metabolism that accompany the behavioral changes occurring when an individual self-administers ethanol. The synthetic pathways for the amino acid and biogenic amine neurotransmitters will be investigated in a rodent self-administration model. The purpose for the Senior Scientist application is to obtain enough research time to allow me to add the neurotransmitter metabolism study while I maintain current effort on my liver-ethanol program.